Transglutaminases (TGases, EC 2.3.2.13) are calcium-dependent enzymes that catalyze the intermolecular cross-linking of certain proteins through the formation of γ-glutamyl-ε-lysine side chain bridges. In mammals, three types of TGases have been characterized to date and are found in tissue, plasma and epidermis. Tissue TGases are involved in diverse biological processes such as endocytosis, apoptosis and cell growth regulation. The plasma-soluble form of TGase, Factor XIIIa, stabilizes blood clots by catalyzing the cross-linking of fibrin during hemostasis. Epidermal TGase plays a key role in the synthesis of the cornified envelope of epidermal keratinocytes.
Unregulated, high TGase activities have been linked to physiological disorders involved in disease states such as acne, cataracts, immune system diseases, psoriasis, neuropathy, neurodegenerative disease such as, for example, Alzheimer's disease, Huntington's disease, Parkinson's disease, Celiac disease, cancer metastasis, inflammation, fibrosis, diabetes, autoimmune diseases, lamellar ichthyosis, psoriasis, supranuclear palsy, renal failure. Potent and selective TGase inhibitors offer means for elucidating the roles of TGases in various disease states and may serve as lead compounds for therapeutic development.
In recent years, TGase activity has been shown to be regulated by a number of potential TGase inactivators, including sulfonamides, iodoactetates [i.e. iodoacetamide], isocyanates [i.e. propylisocyanate], thioureas [e.g. 1-(5-aminopentyl)-3-phenylthiourea (3)], acivicin derivatives [e.g. benzyl 1-((3-bromo-4,5-dihydroisoxazol-5-yl)methylcarbamoyl)-2-phenylethylcarbamate], sulfonium methyl ketones, thioacetonyl heterocycles [e.g. 1,4,5-trimethyl-2-[(2-oxopropyl)thio]imidazole] and electrophilic glutamine analogues. Poor selectivity has, however, limited the therapeutic utility of these classes of inhibitors.
Improved affinity for TGase has been displayed by irreversible inhibitors, such as dipeptide-bound 1,2,4-thiadizoles [i.e. Nα-carbobenzyloxy-2-amino-Nδ-(3-methyl-5-[1,2,4]thiadiazolyl)-L-glutamine], α,β-unsaturated amides and epoxides [i.e. Nα-carbobenzyloxy-Nω-acryloyl-L-lysinylglycine and Nα-carbobenzyloxy-Nω-oxiranecarbonylamino-L-lysinylglycine]. These inhibitors are generally selective for tissue TGase, compared to microbial TGase or GGT, a related transpeptidase.
Thieno[2,3-d]pyrimidin-4-one acylhydrazide derivatives have recently been reported (Duval, E. et al Bioorg. Med. Chem. Lett. 2005, 15, 1885) to be reversible and potent inhibitors of tissue transglutaminase (TG2). An initial structure-activity relationship study for this class of TG2 inhibitors revealed that the acylhydrazide thioether side-chain was important for affinity. Analogs bearing the thiophene ring such as thieno[2,3-d]pyrimidin-4-one acylhydrazide derivatives were among the most potent inhibitors and exhibited slow-binding inhibition.
It is desired to provide further compounds, which can inhibit tissue transglutaminase.